The long term objective of this research is to elucidate and characterize the mechanisms responsible for tissue-specific differential gene expression using the rat Class 3 aldehyde dehydrogenase gene (ALDH-3) as the model system. The mammalian ALDH-3 gene exhibits several aspects of tissue-specific gene expression. Certain normal tissues such as the cornea constitutively express Class-3 ALDH at very high levels. Other tissues such as normal liver express no Class-3 ALDH. In liver induction of Class 3 ALDH activity occurs following both xenobiotic exposure (to TCDD or 3- rnethylcholantherene) and during hepatocarcinogenesis. All evidence indicates both constitutive and inducible regulation of the ALDH 3 gene occurs at the transcriptional level and involves differential use of both cis-acting elements and trans-acting factors.
The specific aims of this proposal are :( l) Complete fine-structure analysis of regulation of the ALDH3 gene in liver and hepatoma cells; (2) Compare regulation of ALDH-3 gene expression in a constitutively expressing tissue, the cornea, to that of liver; (3) Continue assessing physiological roles of Class 3 ALDH in the metabolism of aldehydes generated by cellular oxidative stress. Completion of these specific aims will allow us to understand the molecular basis of differential gene expression under both normal and pathophysiological conditions. The results will, in turn, provide insights into how differential gene expression is related to the physiological role of the gene product.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA021103-14
Application #
2086899
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1979-07-01
Project End
1998-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
14
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of South Dakota
Department
Biochemistry
Type
Schools of Medicine
DUNS #
929930808
City
Vermillion
State
SD
Country
United States
Zip Code
57069
Reisdorph, Richard; Lindahl, Ronald (2007) Constitutive and 3-methylcholanthrene-induced rat ALDH3A1 expression is mediated by multiple xenobiotic response elements. Drug Metab Dispos 35:386-93
Reisdorph, R; Lindahl, R (2001) Aldehyde dehydrogenase 3 gene regulation: studies on constitutive and hypoxia-modulated expression. Chem Biol Interact 130-132:227-33
Canuto, R A; Ferro, M; Salvo, R A et al. (2001) Increase in class 2 aldehyde dehydrogenase expression by arachidonic acid in rat hepatoma cells. Biochem J 357:811-8
Boesch, J S; Miskimins, R; Miskimins, W K et al. (1999) The same xenobiotic response element is required for constitutive and inducible expression of the mammalian aldehyde dehydrogenase-3 gene. Arch Biochem Biophys 361:223-30
Burton, M; Reisdorph, R; Prough, R et al. (1999) Modulation of class 3 aldehyde dehydrogenase gene expression. An eye opening experience. Adv Exp Med Biol 463:165-70
Falkner, K C; Xiao, G H; Pinaire, J A et al. (1999) The negative regulation of the rat aldehyde dehydrogenase 3 gene by glucocorticoids: involvement of a single imperfect palindromic glucocorticoid responsive element. Mol Pharmacol 55:649-57
Canuto, R A; Muzio, G; Ferro, M et al. (1999) Inhibition of class-3 aldehyde dehydrogenase and cell growth by restored lipid peroxidation in hepatoma cell lines. Free Radic Biol Med 26:333-40
Lindahl, R; Xiao, G H; Falkner, K C et al. (1999) Negative regulation of rat hepatic aldehyde dehydrogenase 3 by glucocorticoids. Adv Exp Med Biol 463:159-64
Reisdorph, R; Lindahl, R (1998) Hypoxia exerts cell-type-specific effects on expression of the class 3 aldehyde dehydrogenase gene. Biochem Biophys Res Commun 249:709-12
Prough, R A; Falkner, K C; Xiao, G H et al. (1997) Regulation of rat ALDH-3 by hepatic protein kinases and glucocorticoids. Adv Exp Med Biol 414:29-36

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